Malignant gliomas are highly invasive and neurologically destructive tumors, whose most aggressive manifestation is glioblastoma. The term “glioma” encompasses a group of cancers that includes astrocytomas, oligodendrogliomas, oligoastrocytomas, and ependymomas. The most widely used scheme for classification and grading of glioma is that of the World Health Organization, where gliomas are classified according to their hypothesized line of differentiation, that is whether they display features of astrocytic, oligodendrial or ependymal cells. They are graded on a scale of I to IV according to their degree of malignancies. Glioblastoma (GBM) is classified as grade IV anaplastic astrocytoma.
Glioblastoma is the most common primary brain tumors in the adults. More than half of the 18,000 patients diagnosed with malignant primary brain tumors in US each year have GBM. GBM is an anaplastic, highly cellular tumor, with high proliferation indices, microvascular proliferation and focal necrosis. Signs and symptoms depend on several factors (size, rate of growth, localization of the tumor within the brain) and are mainly represented by headache, seizures, neurological deficits, changes in mental status. GBM prognosis remains dismal. Survival time is less than 2 years for the majority of patients. Karnofsky performance status (KPS) is one of the most important prognostic factors: patients with KPS>70 are alive at 18 months in approx 18% of cases, compared with 13% of patients with lower KPS scores. Primary GBM develops de novo from glial cells, typically has a clinical history of less than six months, is more common in older patients and presents small-cell histology. Secondary GBM develops over months or years from pre-existing low-grade astrocytomas, predominantly affects younger people and presents giant-cell histology.
The molecular biology of gliomas has provided new insights into the development of this disease and control of the disregulation of cell signal pathways through molecularly targeted therapies is the new therapeutic frontier.
Multiple genetic changes are involved in the development of primary and secondary GBMs and the same genetic pathways are dismantled in both primary and secondary tumors.
The main pathways involved in GBM pathogenesis are two [Rich J N, Bigner D D. Nat Rev Drug Discov 2004; 3(5): 430-46]. The first is the signalling pathway mediated by tyrosine kinase growth factor receptors: the ras-MAP kinase signal transduction cascade is activated in nearly all GBMs and Akt is activated in approximately 70% of GBMs. Indeed, amplification of many tyrosine kinase receptors has also been reported [Puputti M et al. Mol Cancer Res 2006; 4(12): 927-934].
The second pathway frequently disrupted in this pathology, as well as in many other human cancers, is the RB-CDK-CDKI (cyclin-dependent kinase inhibitor) regulatory circuit: loss of INK4A (also known as p16) is detected in 40-57% of GBMs and loss of the tumor suppressor Retinoblastoma (RB) is identified in 14-33% of GBMs. In total, mutations in INK4A/CDK2/RB are detected in more than 80% of GBMs and in 50% of anaplastic astrocytomas [Zhu Y and Parada L F. Nature Reviews Cancer 2002; 2: 616-626].
Current therapeutic options for GBM include surgery, radiotherapy and chemotherapy. Drugs most widely used are carmustine, lomustine, vincristine, procarbazine, carboplatin, etoposide and irinotecan. Neoadjuvant or adjuvant therapy with these drugs was shown to prolong disease-free survival but not overall survival.
Concurrent temozolomide (TMZ) and radiotherapy (RT) has now become the new standard of care for patients with newly diagnosed GBM, with a clinically meaningful improvement in survival compared to RT alone (median survival time of 15 months for patients treated with TMZ/RT versus 12 months for patients treated with RT alone; 2-year survival rate of 26% for the TMZ/RT group versus 10% for the RT group.
In spite of the successful introduction of TMZ, clinicians concur that further research for the development of new agents active in glioma is warranted. Indeed, there is still an unmet medical need for new potent agents for the treatment of gliomas. The present invention addresses this problem.